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Tumor Spreading to the Contralateral Ovary in Bilateral Ovarian Carcinoma Is a Late Event in Clonal Evolution
Francesca Micci,Lisbeth Haugom,Terje Ahlquist,Vera M. Abeler,Claes G. Trope,Ragnhild A. Lothe,Sverre Heim
Journal of Oncology , 2010, DOI: 10.1155/2010/646340
Abstract: Cancer of the ovary is bilateral in 25%. Cytogenetic analysis could determine whether the disease in bilateral cases is metastatic or two separately occurring primary tumors, but karyotypic information comparing the two cancerous ovaries is limited to a single report with 11 informative cases. We present a series of 32 bilateral ovarian carcinoma cases, analyzed by karyotyping and high-resolution CGH. Our karyotypic findings showed that spreading to the contralateral ovary had occurred in bilateral ovarian cancer cases and that it was a late event in the clonal evolution of the tumors. This was confirmed by the large number of similar changes detected by HR-CGH in the different lesions from the same patient. The chromosomal bands most frequently involved in structural rearrangements were 19p13 (n=12) and 19q13 (n=11). The chromosomal bands most frequently gained by both tumorous ovaries were 5p14 (70%), 8q23-24 (65%), 1q23-24 (57%), and 12p12 (48%), whereas the most frequently lost bands were 17p11 (78%), 17p13 (74%), 17p12 (70%), 22q13 (61%), 8p21 and 19q13 (52%), and 8p22-23 (48%). This is the first time that 5p14 is seen gained at such a high frequency in cancer of the ovary; possibly oncogene(s) involved in bilateral ovarian carcinogenesis or tumor progression may reside in this band.
Genomic aberrations in borderline ovarian tumors
Francesca Micci, Lisbeth Haugom, Terje Ahlquist, Hege K Andersen, Vera M Abeler, Ben Davidson, Claes G Trope, Ragnhild A Lothe, Sverre Heim
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-21
Abstract: We report a series of borderline ovarian tumors (n = 23) analyzed by G-banding and karyotyping as well as high resolution CGH; in addition, the tumors were analyzed for microsatellite stability status and by FISH for possible 6q deletion.All informative tumors were microsatellite stable and none had a deletion in 6q27. All cases with an abnormal karyotype had simple chromosomal aberrations with +7 and +12 as the most common. In three tumors with single structural rearrangements, a common breakpoint in 3q13 was detected. The major copy number changes detected in the borderline tumors were gains from chromosome arms 2q, 6q, 8q, 9p, and 13q and losses from 1p, 12q, 14q, 15q, 16p, 17p, 17q, 19p, 19q, and 22q. The series included five pairs of bilateral tumors and, in two of these pairs, informative data were obtained as to their clonal relationship. In both pairs, similarities were found between the tumors from the right and left side, strongly indicating that bilaterality had occurred via a metastatic process. The bilateral tumors as a group showed more aberrations than did the unilateral ones, consistent with the view that bilaterality is a sign of more advanced disease.Because some of the imbalances found in borderline ovarian tumors seem to be similar to imbalances already known from the more extensively studied overt ovarian carcinomas, we speculate that the subset of borderline tumors with detectable imbalances or karyotypic aberrations may contain a smaller subset of tumors with a tendency to develop a more malignant phenotype. The group of borderline tumors with no imbalances would, in this line of thinking, have less or no propensity for clonal evolution and development to full-blown carcinomas.Borderline ovarian tumors are of low malignant potential. They exhibit more atypical epithelial proliferation than is seen in adenomas, their benign counterpart, but are without the destructive stromal invasion characteristic of overt adenocarcinomas [1]. Although the cl
DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets
Qinghua Wu, Ragnhild A Lothe, Terje Ahlquist, Ilvars Silins, Claes G Tropé, Francesca Micci, Jahn M Nesland, Zhenhe Suo, Guro E Lind
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-45
Abstract: Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of HOXA9, RASSF1A, APC, CDH13, HOXB5, SCGB3A1 (HIN-1), CRABP1, and MLH1 was found in 51% (26/51), 49% (23/47), 24% (12/51), 20% (10/51), 12% (6/52), 10% (5/52), 4% (2/48), and 2% (1/51) of the carcinomas, respectively, whereas ADAMTS1, MGMT, NR3C1, p14ARF, and p16INK4a were unmethylated in all samples. The methylation frequencies of HOXA9 and SCGB3A1 were higher among relatively early-stage carcinomas (FIGO I-II) than among carcinomas of later stages (FIGO III-IV; P = 0.002, P = 0.020, respectively). The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, HOXA9 hypermethylation was more common in tumours from patients older than 60 years of age (15/21) than among those of younger age (11/30; P = 0.023). Finally, there was a significant difference in HOXA9 methylation frequency among the histological types (P = 0.007).DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and HOXA9, HOXB5, SCGB3A1, and CRABP1 are identified as novel hypermethylated target genes in this tumour type.Ovarian cancer is often not detected until it has reached an advanced stage and is therefore among the most lethal gynaecological cancer diseases. Tumour stage at diagnosis, residual disease following cytoreductive surgery, and performance status which is evaluated by Karnofsky Index [1] are the three major prognostic factors [2]. Epithelial ovarian carcinoma accounts for over 90% of all cases and includes the following major histological subtypes: serous-, mucinous-, endometrioid-, and clear cell- carcinomas. In Norway, more than 90% of patients with ovarian carcinoma are older than 40 years, with a peak incidence at the age of 75–79 [3].A number of genetic changes have been shown to accumulate during carcinogenesis, including DNA co
The Influence of Optimistic Expectations and Negative Life Events on Somatic Symptoms among Adolescents: A One-Year Prospective Study  [PDF]
Terje Arnfinn Murberg
Psychology (PSYCH) , 2012, DOI: 10.4236/psych.2012.32018
Abstract: This study prospectively examined the main effect of optimism on subsequent somatic symptomatology as well as optimism as moderating factors in the link between negative life events and somatic symptoms in a sample of 198 (111 females, 87 males) students in a Norwegian senior high school. Results from the longitudinal multivariate analyses, indicated that the scores for optimism and negative life events were significantly associated with scores of somatic symptoms at time-point two (T2). Moreover, a significant Optimism × Negative life events interaction was found in predicting somatic symptoms. Implications of these findings are discussed.
Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin
Manuela Pinheiro, Terje Ahlquist, Stine A Danielsen, Guro E Lind, Isabel Veiga, Carla Pinto, Vera Costa, Luís Afonso, Olga Sousa, Maria Fragoso, Lúcio Santos, Rui Henrique, Paula Lopes, Carlos Lopes, Ragnhild A Lothe, Manuel R Teixeira
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-587
Abstract: Constitutional and tumor DNA from a test series of 37 patients with rectal and 25 patients with sigmoid carcinomas, previously analyzed for microsatellite instability (MSI), was studied for BAX, IGF2R, TGFBR2, MSH3, and MSH6 microsatellite sequence alterations, BRAF and KRAS mutations, and MLH1 promoter methylation. The findings were then compared with those of an independent validation series consisting of 36 MSI-H carcinomas with origin from each of the large bowel regions. Immunohistochemical and germline mutation analyses of the mismatch repair system were performed when appropriate.In the test series, IGFR2 and BAX mutations were present in one and two out of the six distal MSI-H carcinomas, respectively, and no mutations were detected in TGFBR2, MSH3, and MSH6. We confirmed these findings in the validation series, with TGFBR2 and MSH3 microsatellite mutations occurring less frequently in MSI-H rectal and sigmoid carcinomas than in MSI-H colon carcinomas elsewhere (P = 0.00005 and P = 0.0000005, respectively, when considering all MSI-carcinomas of both series). No MLH1 promoter methylation was observed in the MSI-H rectal and sigmoid carcinomas of both series, as compared to 53% found in MSI-H carcinomas from other locations (P = 0.004). KRAS and BRAF mutational frequencies were 19% and 43% in proximal carcinomas and 25% and 17% in rectal/sigmoid carcinomas, respectively.The mechanism and the pattern of genetic changes driving MSI-H carcinogenesis in distal colon and rectum appears to differ from that occurring elsewhere in the colon and further investigation is warranted both in patients with sporadic or hereditary disease.Colorectal cancer is the third most common neoplasia in the Western world, preceded only by lung cancer in male and breast cancer in female [1]. Approximately 25 to 35% of colorectal cancers are located in the rectum. Multiple differences between cancer of the right and left colon and rectum with regard to epidemiological, clinical behavior,
Hypermethylated MAL gene – a silent marker of early colon tumorigenesis
Guro E Lind, Terje Ahlquist, Matthias Kolberg, Marianne Berg, Mette Ekn?s, Miguel A Alonso, Anne Kallioniemi, Gunn I Meling, Rolf I Skotheim, Torleiv O Rognum, Espen Thiis-Evensen, Ragnhild A Lothe
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-13
Abstract: Using methylation-specific polymerase chain reaction (MSP) the promoter methylation status of MAL was analyzed in 218 samples, including normal mucosa (n = 44), colorectal adenomas (n = 63), carcinomas (n = 65), and various cancer cell lines (n = 46). Direct bisulphite sequencing was performed to confirm the MSP results. MAL gene expression was investigated with real time quantitative analyses before and after epigenetic drug treatment. Immunohistochemical analysis of MAL was done using normal colon mucosa samples (n = 5) and a tissue microarray with 292 colorectal tumors.Bisulphite sequencing revealed that the methylation was unequally distributed within the MAL promoter and by MSP analysis a region close to the transcription start point was shown to be hypermethylated in the majority of colorectal carcinomas (49/61, 80%) as well as in adenomas (45/63, 71%). In contrast, only a minority of the normal mucosa samples displayed hypermethylation (1/23, 4%). The hypermethylation of MAL was significantly associated with reduced or lost gene expression in in vitro models. Furthermore, removal of the methylation re-induced gene expression in colon cancer cell lines. Finally, MAL protein was expressed in epithelial cells of normal colon mucosa, but not in the malignant cells of the same type.Promoter hypermethylation of MAL was present in the vast majority of benign and malignant colorectal tumors, and only rarely in normal mucosa, which makes it suitable as a diagnostic marker for early colorectal tumorigenesis.Epigenetic changes – non-sequence-based alterations that are inherited through cell division [1] – are frequently seen in human cancers, and likewise as genetic alterations they may lead to disruption of gene function. In colorectal cancer, several tumour suppressor genes have been identified to be epigenetically inactivated by CpG island promoter hypermethylation, including the DNA mismatch repair gene MLH1 [2-4], the gatekeeper APC [5], and the cell cycle inhibito
Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas
Guro E Lind, Stine A Danielsen, Terje Ahlquist, Marianne A Merok, Kim Andresen, Rolf I Skotheim, Merete Hektoen, Torleiv O Rognum, Gunn I Meling, Geir Hoff, Michael Bretthauer, Espen Thiis-Evensen, Arild Nesbakken, Ragnhild A Lothe
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-85
Abstract: Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel.Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa.The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.Colorectal cancer is the third most common cancer type in the US and is a major contributor to cancer-death [1]. Most cases of colorectal cancer develop from benign precursors (adenomas) during a long time interval. This provides a good opportunity for detection of colorectal cancer at an early curable stage and to screen for potentially pre-malignant adenomas [2]. Both flexible sigmoidoscopy and the Fecal Occult Blood Test (FOBT) have been tested in randomized trials and shown to reduce mortality from colorectal cancer [3]. By sigmoidoscopy adenomas may be detected and removed and thus the incidence of cancer will be reduced [4], however, this screening is invasive and cumbersome for the patient. FOBT on the other hand is non-invasive and currently the most commonly used screening test for colorectal cancer in Europe. Although the sensitivity and specificity measurements of FOBT have been
Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers
Terje Ahlquist, Guro E Lind, Vera L Costa, Gunn I Meling, Morten Vatn, Geir S Hoff, Torleiv O Rognum, Rolf I Skotheim, Espen Thiis-Evensen, Ragnhild A Lothe
Molecular Cancer , 2008, DOI: 10.1186/1476-4598-7-94
Abstract: The methylation status of eleven genes (ADAMTS1, CDKN2A, CRABP1, HOXA9, MAL, MGMT, MLH1, NR3C1, PTEN, RUNX3, and SCGB3A1) was determined in 154 tissue samples including normal mucosa, adenomas, and carcinomas of the colorectum. The gene-specific and widespread methylation status among the carcinomas was related to patient gender and age, and microsatellite instability status. Possible CIMP tumors were identified by comparing the methylation profile with microsatellite instability (MSI), BRAF-, KRAS-, and TP53 mutation status.The mean number of methylated genes per sample was 0.4 in normal colon mucosa from tumor-free individuals, 1.2 in mucosa from cancerous bowels, 2.2 in adenomas, and 3.9 in carcinomas. Widespread methylation was found in both adenomas and carcinomas. The promoters of ADAMTS1, MAL, and MGMT were frequently methylated in benign samples as well as in malignant tumors, independent of microsatellite instability. In contrast, normal mucosa samples taken from bowels without tumor were rarely methylated for the same genes. Hypermethylated CRABP1, MLH1, NR3C1, RUNX3, and SCGB3A1 were shown to be identifiers of carcinomas with microsatellite instability. In agreement with the CIMP concept, MSI and mutated BRAF were associated with samples harboring hypermethylation of several target genes.Methylated ADAMTS1, MGMT, and MAL are suitable as markers for early tumor detection.Most cases of colorectal cancer (CRC) originate from adenomas. The malignant potential of adenomas increases with size, grade of dysplasia, and degree of villous components,[1] along with the number and order of genetic and epigenetic aberrations.[2] The majority (~85%) of the sporadic carcinomas are characterized by chromosomal aberrations, referred to as a chromosomal unstable (CIN) phenotype, whereas the smaller group (~15%) typically show microsatellite instability (MSI) caused by defect DNA mismatch repair.[2] Most CIN tumors are microsatellite stable (MSS). A third molecular phenotyp
The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)
Terje Sagvolden
Behavioral and Brain Functions , 2006, DOI: 10.1186/1744-9081-2-41
Abstract: The present study tested behavioral effects of guanfacine at doses of 0.075, 0.15, 0.30 and 0.60 mg base/kg i.p. in both male SHRs and their controls, the Wistar Kyoto rat (WKY). ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness.The striking impulsiveness, overactivity, and reduced sustained attention during baseline conditions in the SHR improved by treatment with guanfacine. The most pronounced improvement in SHR behavior was seen following the two highest doses (0.3 and 0.6 mg/kg) of guanfacine when SHR behaviors virtually normalized. The positive effects of the drug were most marked towards the end of the session.The results indicate that guanfacine improved poor noradrenergic modulation of neuronal circuits that involve the frontal lobes in an animal model of ADHD. The present results support the beneficial effects of guanfacine on ADHD behavior reported clinically and experimentally in primate models of frontal function. It is likely that guanfacine improved prefrontal functions in the SHR. It cannot be concluded, however, that the effects of the drug are mediated solely by norepinephrine.Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a cognitive developmental disorder where all clinical criteria are behavioral [1]. Overactivity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms.There have been many attempts to explain the origins of ADHD symptoms. A dual-process model [2-5] suggests that less efficient reinforcement processes and deficient extinction of previously reinforced behavior are fundamental to the problems described as response inhibition [6] and poor executive functions [7].ADHD is highly heritable and the genetic and neurobiological causes are likely to reside in brain catecholaminergic systems (for a review see [4]). Most likely, ADHD symptoms are associated with dysregulation of dopaminergic and noradrenergic modu
Impulsiveness, overactivity, and poorer sustained attention improve by chronic treatment with low doses of l-amphetamine in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD)
Terje Sagvolden
Behavioral and Brain Functions , 2011, DOI: 10.1186/1744-9081-7-6
Abstract: The present study tested the behavioral effects of 0.75 and 2.2 mg l-amphetamine base/kg i.p. in male SHRs and their controls, the Wistar Kyoto rat (WKY). ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness.The striking impulsiveness, overactivity, and poorer sustained attention seen during baseline conditions in the SHR were improved by chronic treatment with l-amphetamine. The dose-response curves were, however, different for the different behaviors. Most significantly, the 0.75 mg/kg dose of l-amphetamine improved sustained attention without reducing overactivity and impulsiveness. The 2.2 mg/kg dose improved sustained attention as well as reduced SHR overactivity and impulsiveness.The effects of l-amphetamine to reduce the behavioral symptoms of ADHD in the SHR were maintained over the 14 days of daily dosing with no evidence of tolerance developing.Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a cognitive developmental disorder where all clinical criteria are behavioral [1]. Overactivity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms.There have been many attempts to explain the origins of ADHD symptoms. A dual-process theory [2-5] suggests that less efficient reinforcement processes and deficient extinction of previously reinforced behavior may explain behavioral changes often described as response disinhibition [6] or poor executive functioning [7].ADHD is highly heritable and the genetic and neurobiological causes are likely to reside in brain catecholamines (for a review see [4]). Most likely, ADHD symptoms are associated with reduced post-synaptic efficacy of dopaminergic and noradrenergic modulation of neuronal circuits that involve the frontal lobes [8,9]. Imaging of striatal neuronal networks indicates reduced dopamine efficacy in ADHD [10]. Further, noradrenergic systems are involved in attention processes and prime p
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